Benzamide-substituted bicyclic imidazo- and pyrazolo-fused -pyridine, -pyrimide, and -pyridazine compounds for treatment of inflammatory diseases

Abstract

The present invention discloses compounds according to Formula I: wherein R 1a , R 1b , R 1c , R 2a , W 1 , W 2 , X 1 , X 2 , X 3 , Y, and Z are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

The invention claimed is: 
     
       1. A compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein, 
         W 1  is N or CR 3  and W 2  is N or CH, with the proviso that W 1  and W 2  cannot both be N; 
         one of X 1 , X 2  and X 3  is N and the other two are C; 
         Y is N or CR 2b ; 
         Z is
 —NR 4a R 4b , 
 —R 4c —, wherein the N atom and R 2a  together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one double bond, or 
 N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 5  groups; 
 
         R 1a  is selected from
 H, 
 halo, 
 —OH, 
 —CN, 
 C 1-6  alkyl optionally substituted with one or more independently selected R 6 , 
 C 1-4  alkoxy optionally substituted with one or more —OH or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, 
 —C(O)—R 7 , 
 —NR 8a R 8b , 
 —S(═O) 2 —C 1-4  alkyl, 
 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4  alkyl, and 
 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S; 
 
         R 1b  and R 1c  are independently selected from
 halo, 
 —OH, 
 —CN, 
 C 1-4  alkyl optionally substituted with one or more independently selected —OH, —CN, or C 2-4  alkenyl, 
 C 3-7  cycloalkyl, 
 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 9  groups, and 
 —NR 10a R 10b , 
 
         or R 1b  and R 1c  together with the atom onto which they are attached form a C 3-6  cycloalkyl, 
         or R 1b  and R 1c  together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 11  groups; 
         R 2a  and R 2b  are independently selected from
 halo, 
 C 1-4  alkyl, 
 C 1-4  alkoxy optionally substituted with one or more independently selected halo, —OH, or C 1-4  alkoxy, 
 —NR 12a R 12b , and 
 —OH; 
 
         R 3  is H, halo, or C 1-4  alkoxy optionally substituted with one or more independently selected —OH or C 1-4  alkoxy; 
         R 4a  is H or C 1-4  alkyl; 
         R 4b  is selected from
 C 1-6  alkyl optionally substituted with one or more independently selected R 13 , 
 C 3-7  cycloalkyl optionally substituted with one or more independently selected R 14a , 
 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 14b , and 
 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4  alkyl; 
 
         R 4c  is H, C 3-7  cycloalkyl, or C 1-6  alkyl optionally substituted with one or more independently selected halo or —CN; 
         each R 5  is independently selected from
 oxo, 
 halo, 
 —CN, 
 —OH, 
 —NR 15a R 15b , 
 phenyl, 
 C 3-7  cycloalkyl, 
 C 2-4  alkynyl, 
 —C(═O)—C 1-4  alkoxy, 
 C 1-4  alkoxy optionally substituted with one or more independently selected halo or phenyl, 
 C 1-4  alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4  alkoxy, and 
 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S; 
 
         each R 6  is independently selected from
 halo, 
 —O—R 16 , 
 —NR 17a R 17b , 
 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, and 
 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; 
 
         R 7  is —OH, C 1-4  alkyl, C 1-4  alkoxy, —NR 18a R 18b , or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more —OH; 
         R 8a  and R 8b  are independently H, —C(═O)—C 1-4  alkoxy, or C 1-4  alkyl optionally substituted with one or more independently selected halo, —CN or —OH; 
         each R 9  is independently halo, —OH, or C 1-4  alkyl optionally substituted with one or more —OH; 
         each R 10a  and R 10b  is independently H or C 1-4  alkyl optionally substituted with one or more —OH; 
         each R 11  is independently selected from
 C 1-4  alkyl optionally substituted with one or more independently selected-CN or C 1-4  alkoxy, 
 —C(═O)—C 1-6  alkyl, and 
 —C(═O)—C 1-6  alkoxy; 
 
         each R 12a  and R 12b  is independently H or C 1-4  alkyl optionally substituted with one —OH or C 1-4  alkoxy; 
         each R 13  is independently selected from
 halo, 
 —CN, 
 —NR 19a R 19b , 
 —OH, 
 C 1-4  alkoxy, 
 C 3-7  cycloalkyl, 
 —S(═O) 2 —C 1-4  alkyl, 
 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and 
 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4  alkyl; 
 
         each R 14a  and R 14b  is independently selected from
 halo, 
 oxo, 
 C 1-4  alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4  alkoxy, 
 —OH, 
 C 1-4  alkoxy, and 
 —NR 20a R 20b ; 
 
         each R 15a  and R 15b  is independently H, C 1-4  alkyl, or —C(═O)—C 1-4  alkoxy; 
         each R 16  is independently selected from
 H, 
 —S(═O) 2 —C 1-4  alkyl, 
 C 1-4  alkyl optionally substituted with one or more —C(═O)—NR 21a R 21b  or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and 
 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S; 
 
         each R 17a  and R 17b  is independently H or C 1-4  alkyl optionally substituted with one or more independently selected-OH or C 1-4  alkoxy; 
         R 18a  and R 18b  are independently H or C 1-4  alkyl optionally substituted with one or more independently selected —OH or C 1-4  alkoxy; 
         each R 19a , R 19b , R 20a , R 20b , R 21a , and R 21b  is independently H or C 1-4  alkyl; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein W 1  is CR 3 , and R 3  is H. 
     
     
       3. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein Y is CR 2b  and R 2b  is C 1-4  alkoxy. 
     
     
       4. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 2a  is —O—CH 3 , substituted with one, two, or three independently selected halo. 
     
     
       5. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein Z is —NR 4a R 4b , and R 4a  is H. 
     
     
       6. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein the compound is according to Formula IIIa, IIIb, IIIc, or IIId: 
       
         
           
           
               
               
           
         
       
     
     
       7. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1b  and R 1c  together with the atom onto which they are attached form a cyclobutyl. 
     
     
       8. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1b  and R 1c  together with the atom onto which they are attached form an oxetanyl or tetrahydropyranyl. 
     
     
       9. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein the compound is according to Formula IVe, IVf, IVg, or IVh: 
       
         
           
           
               
               
           
         
       
     
     
       10. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 4b  is cyclopropyl or 2-fluorocyclopropyl. 
     
     
       11. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1a  is H, —OH, or —CN. 
     
     
       12. A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1a  is C 1-6  alkyl substituted with one —OH. 
     
     
       13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
       14. A method for prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases, comprising administering a compound or pharmaceutically acceptable salt thereof, according to  claim 1 , to a human in need thereof. 
     
     
       15. A method for prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases, comprising administering a pharmaceutical composition of  claim 13  to a human in need thereof.